Human microRNA miR-197-3p positively regulates HIV-1 virion infectivity through its target DDX52 by stabilizing Vif protein expression

MicroRNAs are a part of the integral regulatory mechanisms found in eukaryotic cells that help in maintaining cellular homeostasis by modulating the expression of target genes. However, during stress conditions like viral infection, the expression profile of the microRNAs change, thereby directly modulating the expression of viral genes and/or indirectly targeting the virus by regulating the host genes. The present study intends to identify previously uncharacterized cellular microRNAs, which are significantly modulated upon HIV-1 infection. With the available microarray data of five independent studies in the NCBI GEO database, 10 common yet functionally uncharacterized microRNAs that are deregulated during HIV-1 infection in humans were identified. Their expression profiles were validated in HIV-1 infected human peripheral blood mononuclear cells and a CD4⁺T cell line. Among them, miR-197-3p showed significant upregulation during HIV-1 infection in all the cell types tested and was selected for further characterization. We then found that miR-197-3p increases progeny virion infectivity through restricting the expression of DDX52. Interestingly, DDX52 showed a negative impact on virion infectivity by downregulating the HIV-1 viral infectivity factor (Vif) at the protein level. Mechanistically, our study also revealed that Vif, DDX52, and APOBEC3G form a complex, which might be responsible for Vif downregulation by proteasomal degradation. Taken together, our results demonstrate that miR-197-3p is a positive regulator of HIV-1 infectivity as it enhances the progeny virion infectivity by targeting DDX52, which is a negative regulator of Vif.